The recent discovery of the p53 homolog, p73, and its localization to the lp36.3 locus deleted in neuroblastoma, breast, colon, and brain cancer seemed to assure a role for p73 alongside p53 in tumor suppression. Countering this hypothesis, however, was the finding that the remaining p73 allele in tumors was wildtype, and that mice lacking both copies of p73 did not show an increase in tumorigenesis. More recently, however, a wealth of data has implicated p73 in DNA damage responses, apoptotic pathways, and as a collaborator with p53. In addition, our mouse models show, paradoxically, that the loss of a single p73 allele, though not the loss of both copies, contributes to tumorigenesis. It is likely that the mechanism behind this unusual result is rooted in the intriguing structural features of the p73 gene, which give rise to both transactivating (TA) p73 products as well as N-terminally truncated (AN),"dominant-negative" isotypes that antagonize p73 and other members of the p53 family. This is a proposal to use mouse models, biochemistry, and cell biology strategies to determine p73's interaction with the p53 gene family, and its impact on tumorigenesis. Specifically, we aim to answer three questions: (1) What is the molecular mechanism for tumorigenesis in mice showing LOH for p73? (2) What are the consequences of selectively deleting either of the apparently contradictory transactivating and dominant negative p73 isotypes for tumorigenesis? (3) Are the p73 and p63 genes interacting with, or required by, p53 in cellular damage response pathways, and can we model these interactions in an in vivo system that would report consequences in tumorigenesis, development, and cellular differentiation? We anticipate that the data generated in this research will answer whether p73 is a tumor suppressor or proto-oncogene, the degree of physiological interactions amongst the p53 family members, and the degree to which the major tumor suppressor p53 depends on p73 for its remarkable functions in the cell. As p73 LOH is a common feature of various cancers in humans, this proposal aims to determine the significance of this event and strategies for countering disruptions in the p53 family that lead to oncogenesis.